Stroke affects 500,000 people a year, of whom 150,000 will die, making it the leading cause of death, and one of the major causes of neurological disability, in the United States . Of those who survive a stroke, there is significant chance of major disability. It is estimated that more than 26 billion dollars are spent each year on direct medical costs for stroke survivors. The great majority of strokes (>80%) are ischemic in nature. In ischemic stroke, a large portion of the neural damage occurs not as a result of the initial insult, but in the following hours and days. Recent evidence suggests that this delayed neuronal death is an apoptotic process in which caspase 3 plays a critical role. Thus, caspase 3 inhibition may provide a novel treatment modality for ischemic stroke. This program will apply a proprietary drug discovery technology (TRAP) to identify small molecule caspase 3 inhibitors. Based on these inhibitors, a medicinal chemistry effort will produce compounds with sufficient potency and specificity to test, using animal models, the hypothesis that caspase 3 inhibition is effective against transient brain ischemia as well as to serve as starting points for the development of drugs to treat stroke in humans. PROPOSED COMMERCIAL APPLICATIONS: Compounds that diminish neuronal loss due to an ischemic event will be useful therapeutic agents for the management of strokes.